Vitamin B₁₂ is nontoxic. Deficiency is not uncommon, especially among older adults.

[DFM ] Letter Key

Description

• Cobalamin, a water-soluble vitamin, is almost completely absent in plants. A cobalt-containing coenzyme, cobalamin functions closely with folic acid. In humans, 50% to 90% of the body’s stores are in the liver; it takes years to deplete bodily stores.

Food Sources

• Meats (especially liver and kidney), poultry, dairy products, eggs, and seafoods (especially bivalves). Trace amounts in legumes, soybeans, seaweed, and blue-green algae, including spirulina

Mechanism/Pharmacokinetics

• Involved in methylation reactions; required for methylmalonyl-CoA mutase (which transforms methylmalonyl to succinyl-CoA for degradation of odd-numbered carbon fatty acids) and methionine synthetase, which interacts with methyltetrahydrofolic acid to form trans-homocysteine into methionine.
• Orally ingested cobalamin binds to a carrier protein in saliva and gastric juices and then is released to intrinsic factor, secreted by stomach cells. This complex binds to the brush border of ileal mucosal cells, where it is absorbed.

[Outline]

• DDescription
• FFood Sources
• MMechanism/Pharmacokinetics

[CEAO ] Letter Key

Clinical Trials

• Osteoarthritis
  • A double-blind crossover study in 26 participants (including 23 women) with osteoarthritis of the hands compared placebo with folate (6,400 mcg) or a combination of folate (6,400 mcg) and a very low dose of cobalamin (20 µg) for 2 months each (1). There were no clear differences among groups in grip strength, tender joints, acetaminophen use, or other measures; mean patient assessments did not change from baseline.
• Diabetic neuropathy
  • A randomized placebo-controlled double-blind study of 50 patients with diabetic neuropathy (36 completed) tested the effects of methylcobalamin 500 mg t.i.d. × 4 months on nerve conduction studies and a peripheral neurology score that included somatic symptoms, autonomic symptoms, and clinical signs (2). Compared with baseline, peripheral neurology scores improved significantly in the treated, but not the placebo, group (p < 0.05). Nerve conduction studies did not change.
• Seasonal affective disorder
  • A double-blind, randomized study tested cyanocobalamin in 27 patients with seasonal affective disorder (3). After a 2-week placebo washout, participants received 1.5 mg cyanocobalamin t.i.d. or placebo for 2 weeks. No significant differences were seen between groups in a structured depression rating.

Epidemiologic Studies

• Incontinence
  • A case-control study of 104 matched pairs found that those with B₁₂ deficiency (serum levels less than 250 pg/mL) were 2.63 times as likely to be incontinent than matched controls [p = 0.026, 95% confidence interval (CI) 1.11, 6.44] (4).
• Depression
  • Among 700 disabled, nondemented women older than 65 years, participants with B₁₂ deficiency were 2.05 times as likely to be severely depressed than nondeficient participants (assessed by the geriatric depression scale) (5).
• Impaired hearing/tinnitus
  • In 55 women aged 60 to 71 years, pure-tone averages were inversely correlated with serum B₁₂ and red blood cell folate; participants with impaired hearing had significantly lower serum B₁₂ (38%) and lower red blood cell folate (31%) than women with normal hearing (6).
  • In 113 army personnel, B₁₂ deficiency was significantly more common in those with tinnitus and noise-induced hearing loss (47%) than in those with noise-induced hearing loss only (27%) or in normal subjects (19%) (7).

Animal/In Vitro

• Hydroxycobalamin inhibits HIV-1 infection of human blood monocytes and lymphocytes in vitro (8).

Other Claimed Benefits/Actions

• Asthma
• Bursitis
• Dementia
• Depression
• Diabetic neuropathy
• Multiple sclerosis
• Osteoporosis

[Outline]

• CClinical Trials
  • Osteoarthritis
  • Diabetic neuropathy
  • Seasonal affective disorder
• EEpidemiologic Studies
  • Incontinence
  • Depression
  • Impaired hearing/tinnitus
• AAnimal/In Vitro
• OOther Claimed Benefits/Actions

[AD ] Letter Key

Adverse Reactions

B₁₂ is very safe.

Drug Interactions

• Biguanides: reduce absorption of B₁₂
• Cimetidine: decreases absorption of protein-bound vitamin B₁₂
• Cholestyramine: decreases absorption by binding intrinsic factor
• Colchicine: decreases absorption through disturbing intestinal mucosal function
• Methotrexate: possibly impairs absorption
• Neomycin: decreases absorption
• PAS: decreases absorption
• Potassium chloride (slow-release): inhibits intrinsic factor activity by lowering ileal pH
• Sodium nitroprusside: decreases serum B₁₂ temporarily

[Outline]

• AAdverse Reactions
• DDrug Interactions

[DFFL ] Letter Key

Deficiency Signs and Symptoms

• Macrocytic anemia [mean corpuscular volume (MCV) greater than 100 µ³, hypersegmented neutrophils] (most commonly pernicious anemia), leukopenia, thrombocytopenia, stomatitis, and glossitis (9). Neurologic manifestations may include peripheral neuropathy (often beginning with symmetrical paresthesias of the lower extremities; may include hyporeflexia), spinal cord involvement (resulting in loss of position and vibratory sense, ataxia, weakness, spasticity, urinary and fecal incontinence, impotence, hyperreflexia, clonus, and positive Babinski reflex), autonomic neuropathy (which may present as orthostatic hypotension), and visual impairment (retrobulbar neuritis, optic atrophy, pseudotumor cerebri). Psychiatric manifestations may include dementia, hallucinations, psychosis ("megaloblastic madness"), paranoia, depression, and personality changes (10).
• Risk factors for deficiency
  • Age (deficiency is common in older adults, who should take 3 µg B₁₂ daily)
  • B₁₂ metabolic defect (homocystinuria, B₁₂-responsive methylmalonic acidemia)
  • Partial gastrectomy (decreases intrinsic factor)
  • Ileal resection
  • Pancreatectomy
  • Inflammatory bowel disease
  • Sprue
  • Alcoholism
  • Vegan diet
  • Parasites

Factors Decreasing Availability/Absorption

• Liver disease, severe pancreatic disease, hyperthyroidism, increased hematopoiesis, bacterial overgrowth in the small intestine, excessive soluble fiber intake, anticonvulsants, biguanides, methotrexate, neomycin, para-aminosalicylic acid (PAS), tetracycline, sodium nitroprusside, potassium chloride (slow-release), cimetidine, cholestyramine, and colchicine

Factors Increasing Availability/Absorption

• Nonionic surfactants (polyoxyethylene sorbitans)

Laboratory Tests

• Samples should be collected fasting.
• Plasma B₁₂: normal values 200 to 700 pg/mL; levels less than 150 pg/mL indicate deficiency.
• Competitive binding assays are preferred. Either serum or plasma may be used, but blood tubes containing heparin or fluoride should be avoided (both degrade B₁₂) (11). Falsely low serum B₁₂ levels may be seen with multiple myeloma, malignancy, aplastic anemia, transcobalamin I deficiency recent radioisotope studies, or high dose vitamin C. Falsely normal levels (in the presence of deficiency) may be seen in severe liver disease, chronic granulocytic leukemia, transcobalamin II deficiency, congenital cobalamin coenzyme deficiency, or recent nitrous oxide inhalation (10). Methylmalonic acid and homocysteine levels may be earlier indicators of marginal B₁₂ status. Normal homocysteine range is 7 to 22 µmol/L.
• Schilling test
  • A Schilling test differentiates between B₁₂ deficiency caused by pernicious anemia or intestinal malfunction. After intramuscular administration of 1,000 µg of B₁₂, intestinal absorption of unbound B₁₂ and bound B₁₂ are compared. With intestinal dysfunction, neither isotope is absorbed normally. In pernicious anemia, bound, but not unbound, B₁₂ is well absorbed. Some patients with pernicious anemia can absorb crystalline B₁₂ but not protein-bound B₁₂; these people will have normal Schilling tests unless a "food" Schilling test is done.

[Outline]

• DDeficiency Signs and Symptoms
  • Risk factors for deficiency
• FFactors Decreasing Availability/Absorption
• FFactors Increasing Availability/Absorption
• LLaboratory Tests
  • Schilling test

[MRC ] Letter Key

Mode of Administration

• Vitamin B₁₂ may be administered p.o., i.m., i.v., sublingually, or as an intranasal gel.
• Different forms include cyanocobalamin; hydroxocobalamin; and two coenzyme forms, methylcobalamin and adenosylcobalamin. Methylcobalamin may be more effective than cyanocobalamin. Hydroxycobalamin is best for those with tobacco amblyopia or tropical nutritional amblyopia (12) (see questions and answers).

Recommended Dietary Allowance

Correcting Deficiency

• A dose of 100 to 1,000 µg cyanocobalamin or hydroxycobalamin i.m. × 1, then 100 µg q.d. × several days; 1,000 µg cobalamin p.o. q.d. is also effective.
• For chronic therapy, 1 mg p.o. q.d. or 100 µg i.m. monthly.

[Outline]

• MMode of Administration
• RRecommended Dietary Allowance
• CCorrecting Deficiency

• What is the connection between nitrous oxide and vitamin B₁₂?
• Are all vegetarians deficient in B₁₂?
• Is injected B₁₂ more effective than oral or sublingual B₁₂?
• What is the connection between B₁₂ and homocysteinemia?

Q: What is the connection between nitrous oxide and vitamin B₁₂?

A: Nitrous oxide inactivates cob(I)alamin, and in vitamin B₁₂-deficient patients may cause demyelination, spastic paresis, subacute combined degeneration of the spinal cord, and encephalopathy (13). Debilitated, B₁₂-deficient and possible folate-deficient patients may experience major problems from nitrous oxide; prophylactic supplementation is advised (14).

Q: Are all vegetarians deficient in B₁₂?

A: No. Ova-lacto vegetarians, who consume eggs and dairy products, are not at increased risk of B₁₂ deficiency. Vegans (who consume no animal products) are at higher risk, although adequate B₁₂ may be obtained from a vegan diet if enough sea vegetables and/or fermented products are consumed. In 21 long-term adherents of a strict uncooked vegan ("living food") diet, serum B₁₂ levels were significantly lower than matched controls; more than half fell below the lower reference limit (15).

Vegans consuming nori and/or Chlorella seaweeds had B₁₂ levels twice as high as vegans who did not consume seaweed. Six of nine vegans showed a slow but significant decline in B₁₂ levels over a 2-year observation period.

Q: Is injected B₁₂ more effective than oral or sublingual B₁₂?

A: In some cases, but for most cases of nutritional deficiency, injected B₁₂ is more effective only at low doses. Although B₁₂ injections are more commonly used than oral replacement in the United States, oral cobalamin is just as effective and certainly more convenient. Distrust of oral B₁₂ stems from early studies that showed variable absorption of orally administered B₁₂ (100 to 250 µg). This can easily be resolved, however, by giving higher oral doses of 1,000 µg/day. Some recommend that deficient patients should receive 2,000 µg b.i.d. for the first month to rapidly replenish liver stores.

High doses of sublingual B₁₂ (2,000 µg/day × 7 to 12 days) have been shown to normalize cobalamin concentration in deficient subjects, but there is no proven advantage of this form of administration (16).

There are several cases in which hydroxycobalamin is preferred, although it is available only in parenteral forms. Hydroxocobalamin is a cyanide antagonist (and has been used as an antidote to cyanide poisoning in fire victims) (17). Cyanocobalamin does not bind cyanide. Cyanocobalamin is ineffective for those with tobacco amblyopia or in smokers with pernicious anemia; hydroxycobalamin must be used in these cases (12).

Q: What is the connection between B₁₂ and homocysteinemia?

A: Elevated levels of homocysteine are associated with increased risk of cardiovascular disease (18), stroke (19), deep vein thrombosis (20), and neural tube defects (21). Folic acid is more effective than B₁₂ in lowering homocysteine levels, except when homocysteinemia is due to B₁₂ deficiency. Those with low normal B₁₂ levels may derive maximum benefit from combined therapy. In one trial, 0.4 mg of cyanocobalamin lowered homocysteine concentrations 14.8%; folic acid, however, reduced concentrations by 41.7% (22).

1. Flynn MA, Irvin W, Krause G. The effect of folate and cobalamin on osteoarthritic hands. J Am College Nutr 1994;13:351–356.
2. Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg 1992;94:105–111.
3. Oren DA, Teicher MH, Schwartz PJ et al. A controlled trial of cyanocobalamin (vitamin B12) in the treatment of winter seasonal affective disorder. J Affective Disord 1994;32:197–200.
4. Rana S, D’Amico F, Merenstein JH. Relationship of vitamin B12 deficiency with incontinence in older people. J Am Geriatr Soc 1998;46:931–932.
5. Penninx BWJH, Guralnik JM, Ferrucci L et al. Vitamin B12 deficiency and depression in physically disabled older women: epidemiologic evidence from the Women’s Health and Aging study. Am J Psychiatry 2000;157:715–721.
6. Houston DK, Johnson MA, Nozza RJ et al. Age-related hearing loss, vitamin B12, and folate in elderly women. Am J Clin Nutr 1999;69:564–571.
7. Shemesh Z, Attias J, Ornan M et al. Vitamin B12 deficiency in patients with chronic tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;14:94–99.
8. Weinberg JB, Sauls DL, Misukonis MA et al. Inhibition of productive human immunodeficiency virus-1 infection by cobalamins. Blood 1995;86:1281–1287.
9. Heimburger DC, Weinser RL. Handbook of clinical nutrition, 3rd Ed. Mosby, St. Louis: 1997:192.
10. Clementz GL, Schade SG. The spectrum of vitamin B12 deficiency. Am Fam Pract 1990;41:150–162.
11. Linder MC. Nutritional biochemistry and metabolism, with clinical applications, 2nd ed. East Norwalk, CT: Appleton & Lange, 1991.
12. Freeman AG. Sublingual cobalamin for pernicious anaemia. Lancet 199;354:2080.
13. Lee P, Smith I, Piesowicz A et al. Spastic paraparesis after anaesthesia. Lancet 1999;353:554.
14. Guttormsen AB, Refsum H, Ueland PM. The interaction between nitrous oxide and cobalamin. Biochemical effects and clinical consequences. Acta Anaesthesiol Scand 1994;38:753–756.
15. Rauma A-L, Torronen R, Hanninen O et al. Vitamin B12 status of long-term adherents of a strict vegan diet ("living food diet") is compromised. J Nutr 1995;125:2511–2515.
16. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet 1999;354:740–741.
17. Houeto P, Hoffman JR, Imbert M et al. Relation of blood cyanide to plasma cyanocobalamin concentration after a fixed dose of hydroxocobalamin in cyanide poisoning. Lancet 1995;346:605–608.
18. Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr 1996;126:1276S–1280S.
19. Perry IJ, Refsum H, Morris RW et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395–1398.
20. Den Heijer M, Koster T, Blom HJ et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759–762.
21. Mills JL, McPartlin JM, Kirke PN et al. Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 1995;345:149–151.
22. Ubbink JB, Vermaak WJH, van der Merwe A et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927–1933.